This proposal seeks to establish the relationship between an identified hypothalamic catecholamine abnormality and the obesity syndromes of the genetically obese-diabetic mutants obob and dbdb. Lesions of the hypothalamic norepinephrine systems and the continuous intrahypothalmic infusion of noradrenergic drugs will be used to evaluate the effect of the manipulation of noradrenergic systems on feeding and on body weight in these mutants. The effects of these treatments on the hypothalmus will be neurochemically assessed by assay of catecholamine content and alpha-adrenergic receptor binding. In addition, the nature of the catecholamine defect of the mutants will be further characterized. The anatomical location of the increased norepinephrine levels will be specified by measuring catecholamine content of individual hypothalamic nuclei using a sensitive radio-enzyme assay. Tyrosine hyroxylase activity in brain regions will also be determined. An increase in alpha-adrenergic receptor number has been found in the obob mouse and other receptor systems (e.g., beta-adrenergic, GABA) will be investigated to check for widespread membrane abnormalities. The project will test the possiblity that the elevated brain catecholamines are a secondary effect of peripheral hormonal disturbances. Alloxan treatment and adrenalectomy will be used to reduce insulin and corticosteroid levels and the effects on central catecholamine levels assessed.